Method for synthesizing (E)-Anethol and Related Compounds By Cross Coupling Reaction of Potassium alllyltrifluroborate and 4-bromoanisole and aryl halides

ABSTRACT

Methods of producing substituted and non-substituted beta-methyl styrene by a cross-coupling reaction are provided. The disclosure also provides for methods of preparing (E)-Anethol and related compounds by a cross coupling reaction of potassium allyltrifluoroborate and 4-bromoanisole and aryl halides. Compounds, compositions, and methods of treating disorders utilizing beta-methyl styrene are also provided.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Appl. No.61/399,054, filed Jul. 6, 2010, the content of which is hereinincorporated by reference in its entirety.

FIELD

The disclosure relates to methods of preparing substituted andnon-substituted beta-methyl styrene compounds by a cross-couplingreaction. In an aspect, the disclosure relates to a method of preparing(E)-Anethol by a cross coupling reaction of potassiumallyltrifluoroborate and 4-bromoanisole.

BACKGROUND

(E)-Anethol is a useful organic compound for whose fragrance is widelyused in the fragrance industry for perfumes, scented candles, andnumerous related products. It is also widely used in the production ofalcoholic beverages such as raki, uzo, pernod, anisette, ricard, andgranier where an aromatic fragrance is a part of the beverage'scharacter. In certain countries, (E)-Anethol is used in the food andpharmaceutical industries and recently been investigated as an insectrepellant as well.

Naturally occurring sources of Anethol isomers are found in thevarieties of the anise, camphor, and fennel plants. (E)-Anethol isderived from these plants by a process of crushing and waterdistillation. The resulting amount of (E)-Anethol obtained from thisprocess is quite low—with a 3.5% (E)-Anethol yield considered to be verygood. The demand for the compound, coupled with the inefficient processused to obtain it, has caused others to try and produce a syntheticversion of (E)-Anethol. Until now, those efforts have been unsuccessful.In an aspect, the disclosure provides for a novel, non-obvious anduseful method for synthetically producing beta-methyl styrene compounds.In another aspect, the disclosure provides for a novel, non-obvious anduseful method for synthetically producing (E)-Anethol and relatedcompounds.

Similarly, potassium organotrifluoroborates have been shown to be anindispensable class of transformative organic reagents for wide range ofcross-coupling reactions. The possible combinations of electrophiles andnucleophiles in cross-coupling reactions of allylic metals with aryl,alkenyl, and allyl electrophiles, or their reversed combination, areimportant due to the frequent occurrence of these fragments in naturalproducts. In light of their low toxicity and operational simplicity,attempts have been made to use potassium allyltrifluoroborates asallylating agents. However, until now success in such efforts has beenlargely unknown. In another embodiment of the disclosure (E)-Anethol issynthesized from a palladium catalyst system utilizingmicrowave-enhanced coupling of potassium allyltrifluoroborates and arylhalides.

Transition metal catalyzed cross-coupling reaction method is extensivelyapplied in modern chemistry for carbon-carbon bond formation reaction.Following the recent application of potassium organotrifluoroborates inorganic transformations, further advances of this field especially withmicrowave irradiation in water have recently been made. The instantdescription focuses on the development of a new catalyst system forallylation reactions that involve potassium allyltrifluoroborates,organic halides as electrophiles, water as a solvent, and microwaveactivation.

SUMMARY

In an aspect the disclosure provides for a method of producing a styrenecompound by a reaction comprising, consisting of, or consistingessentially of

reacting a potassium trifluoroborate with an aryl halide compound ofFormula (I)

wherein

X is selected from the group consisting of I, Br, OTf, ONf, ODs, andOAc; and

Z is selected from the group consisting of F, Cl, Br, I, CN, —SO₃H,—CO₂H, —CHO, —NO₂, CF₃, CCl₃, and an alkyl group. In an aspect, thereaction is catalyzed by a palladium salt. In another aspect, thepalladium salt can be selected from the group consisting of Pd(OAc)₂,PdCl₂(dppf)CH₂Cl₂, PdCl₂ (d^(t)bpf), Pd₂(dba)CHCl₃ PdCl₂ (dphos)₂,Pd(dba)₂, PdCl₂ (dtbpf), and Pd(Ph₃)₂.

The disclosure also provides for a method of producing an Anetholcompound, for example, (E)-Anethol, by a method comprising, consistingof, or consisting essentially of reacting a potassiumallyltrifluoroborate with 4-bromoanisole. In another aspect, the methodsdisclosed herein are catalyzed with a palladium salt, for example,Pd(OAc)₂, PdCl₂(dppf)CH₂Cl₂, PdCl₂ (d^(t)bpf), Pd₂(dba)CHCl₃ PdCl₂(dphos)₂, Pd(dba)₂, PdCl₂ (dtbpf), or Pd(Ph₃)₂. In another aspect, themethods described herein further comprise heating potassiumallyltrifluoroborate and said 4-bromoanisole from about 100° C.-150° C.for about 10 to about 60 minutes. In yet another aspect, the methodsdescribed herein can include potassium allyltrifluoroborate and said4-bromoanisole are present in a ratio of about 4:1 to about 1:1 or aratio of about 4:1.

The disclosure also provides for a method of administering a compounddescribed herein, for example, (E)-Anethol, to a patient in need thereofto treat a disorder selected from the group consisting of a viralinfection, HIV, Hepatitis C, herpes simplex virus-1, herpes simplexvirus-2, vesicular stomatitis virus, parainfluenza-3 coxsackie B3, andsindbid virus.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides for a method of preparing (E)-Anethol.

FIG. 2 provides for a method of obtaining a product by the reaction ofpotassium allyltrifluoroborate with 4-bromoiodobenzene in the presenceof a palladium catalyst in isopropanol/water.

FIG. 3 provides for methods of obtaining a product by utilizingdifferent ratios of a palladium catalyst under varied experimentalconditions.

FIG. 4 provides for methods of producing various trans-β-methyl-styrenesproducts.

FIG. 5 provides for an example mechanism for cyclopropanation.

FIG. 6 provides for an example of a coupling product.

FIG. 7 provides for analytical data of beta-methylstyrenes of Table 1.

DETAILED DESCRIPTION SUMMARY

In an aspect, the disclosure provides for a method of producingsubstituted and non-substituted beta-methyl styrene compounds by themethods disclosed herein. In another aspect, as an example, thedisclosure provides for the following reaction:

In an aspect, “Z” may be an electron withdrawing or an electron donatinggroup. In another aspect, “Z” may be a halogen group. In an aspect, “Z”may be an F, Cl, Br, or I. In yet another aspect, “Z” may beindependently selected from a cyano group, such as CN, a sulfonategroup, such as —SO₃H, —CO₂H, an ester group, such as —CO₂R, an aldehydegroup, such as —CHO, a ketone group, such as —COR, a nitro group, suchas —NO_(2,a) quaternary amine/quaternary ammonium base, such as NR₃ ⁺, atrihalide group, such as —CF₃ or CCl₃, or an alkyl group. In anotheraspect, “Z” may be independently selected from methyl, ethyl, propyl,isopropyl, cyclopropyl, butyl, tert-butyl, pentyl, tert-butyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl, substituted or non substitutedC₂-C₁₂-alkyl, substituted or non substituted C₂-C₁₂-alkenyl, substitutedor non substituted C₂-C₁₂-alkynyl, or a (CH₂)₃ ring structure, (CH₂)₄ring structure, (CH₂)₅ ring structure, (CH₂)₆ ring structure, (CH₂)₇ring structure, or (CH₂)₈ ring structure. In an aspect, “R” is selectedfrom the group consisting of methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, tert-butyl, pentyl, tert-butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl, and a substituted or non substitutedC₂-C₁₂-alkyl.

In an aspect, “X” may be a may be a halogen group or may be selectedfrom I, Br, OTf, ONf, ODs, or OAc. In another aspect, “X” is not Cl orF. In an aspect, compound “1” is a potassium trifluoroborate, such aspotassium allyltrifluoroborate. In another aspect, compound “1” is analkyl substituted boronic acid compound.

In another aspect, the disclosure provides for a method of producing(E)-anethol by the following Scheme B:

In an aspect, potassium allyltrifluoroborate and 4-bromoanisole are in aratio of 4:1 in Scheme B.

In an aspect, a beta-methyl styrene is synthesized by apalladium-catalyzed cross-coupling reaction of potassiumallyltrifluoroborate and 4-bromoanisole in water/isopropanol underheating. In another aspect, (E)-anethol is synthesized by apalladium-catalyzed cross-coupling reaction of potassiumallyltrifluoroborate and 4-bromoanisole in water/isopropanol undermicrowave heating. A significant advantage of using potassiumallyltrifluoroborate is that it is stable and can be readily preparedcompared to the corresponding allylboronic esters. In an aspect, thereaction is completed within 30 min with a high yield of (E)-Anetholregioselctively.

In an aspect, methods disclosed herein result in an increased yield ofsubstituted and non-substituted beta-methyl styrene compounds. Inanother aspect, methods disclosed herein result in an increased yield of(E)-Anethol or any one of compounds 3a-3l as set forth in Table 1. In anaspect, the improved yield is relative to conventional methods. Inanother aspect, the improved yield is relative to traditional methods ofpurifying (E)-Anethol, for example, in methods involving crushing plantsand water distillation. In yet another aspect, the yield of the product,for example, substituted and non-substituted beta-methyl styrenecompounds, (E)-Anethol, or any one of compounds 3a-3l as set forth inTable 1, may be from about 5%-99.9%, from about 10%-99%, from about20%-90%, from about 30%-80%, from about 50%-99%, from about 60%-99%,from about 70%-99%, from about 70%-95%, from about 80%-99%, from about90%-99%, greater than 50%, greater than 60%, greater than 70%, greaterthan 80%, greater than 85%, greater than 90%, greater than 95%, greaterthan 95%, about 75%, about 90%, about 95%, about 96%, about 97%, about98%, or about 99%.

In an aspect, the ratio of compound “1” to compound “2” present in thereaction is from about 10:1 to about 1:10, 8:1 to about 1:8, from about5:1 to about 1:5, from about 4:1 to about 1:4, from about 3:1 to about1:3, from about 5:1 to about 3:1, from about 5:1 to about 2:1, fromabout 4:1 to about 3:1, from about 4:1 to about 2:1, from about 4:1 toabout 1:1, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about6:1, or about 10:1. In another aspect, the disclosure provides for aratio of compound “1” to compound “2” of from about 5:1 to about 3:1,from about 5:1 to about 2:1, from about 4:1 to about 3:1, from about 4:1to about 2:1, from about 4:1 to about 1:1, about 1:1, about 2:1, about3:1, or about 4:1 results in a product yield of between about 5%-99.9%,about 10%-99%, about 20%-90%, about 30%-80%, about 50%-99%, about60%-99%, about 70%-99%, about 70%-95%, about 80%-99%, about 90%-99%,greater than 50%, greater than 60%, greater than 70%, greater than 80%,greater than 85%, greater than 90%, greater than 95%, greater than 95%,about 75%, about 90%, about 95%, about 96%, about 97%, about 98%, orabout 99%.

In another aspect, the methods disclosed herein may employ microwave orother conventional heating sources. In an aspect, the methods disclosedherein may employ heating from about 50° C.-250° C., from about 80°C.-200° C., from about 100° C.-180° C., from about 100° C.-150° C., fromabout 100° C.-140° C., from about 100° C.-130° C., from about 110°C.-130° C., about 100° C., about 110° C., about 120° C., about 130° C.,about 140° C., about 150° C. In another aspect, the methods disclosedherein may employ any of the above temperatures for a time period offrom about 10 minutes to about 4 hours, from about 10 minutes to about 2hours, from about 10 minutes to about 60 minutes, and from about 20minutes to about 40 minutes. In yet another aspect, the methodsdisclosed herein may employ microwave or conventional heating from about10 minutes to about 4 hours, from about 10 minutes to about 2 hours,from about 10 minutes to about 60 minutes, and from about 20 minutes toabout 40 minutes.

In an aspect, potassium allyltrifluoroborate is treated with4-bromoiodobenzene in the presence of a palladium catalyst inisopropanol/water (IPA/water) under microwave irradiation. Under such acondition, for example, a coupling product as set forth in FIG. 2/Scheme1 was obtained. In another aspect, to obtain an efficient catalyst forhomoallylation reactions using potassium allyltrifluoroborates and arylhalides, various palladium salts such as Pd(OAc)₂, PdCl2(dppf)CH₂Cl₂,Pd2(dba)₃CHCl₃, PdCl2(dphos)₂, Pd(dba)₂, PdCl2(dtbpf), and Pd(Ph3P)₄ andligands such as dppb, dppf, Ph3P, and dppe were introduced.

In another aspect, a base may be used with the methods disclosed herein.In an aspect, the base may be KF, Cs2CO3, K2CO3, KOH, and iPr2NEt;solvents such as water, IPA/water, and THF/water. FIG. 3 (Scheme 2)details different reaction conditions obtained by using both microwaveheating and conventional heating.

In another aspect, the disclosure provides for a method of utilizinganethol, (E)-anethol, or any one of compounds 3a-3l as set forth inTable 1 either alone, or in combination with other chemical compounds,in a method for treating cancer or cancerous tumors. In another aspect,the disclosure provides for a method of utilizing anethol, (E)-anethol,or any one of compounds 3a-3l as set forth in Table 1 either alone, orin combination with other chemical compounds, in a method for treatingviral infections, including but not limited to HIV, Hepatitis C andherpes simplex virus-1, herpes simplex virus-2, vesicular stomatitisvirus, parainfluenza-3 coxsackie B3, and sindbid virus. In anotheraspect, compounds disclosed herein, either alone or in combination withappropriate cancer treating compositions or compounds, may be employedin a method for treating cancer or cancerous tumors wherein thecompounds are injected into the body of the person being treated at ornear the location of the tumor, introduced into the body orally or inthe form of a liquid, or are introduced into the body orally in the formof a solid capsule. In another aspect, any of the compounds describedherein may be injected into the body of the person being treated at ornear the location of a tumor, introduced into the body orally or in theform of a liquid, or are introduced into the body orally in the form ofa solid capsule.

The disclosure also provides for methods of producing the disclosedcompounds comprising, consisting of, or consisting essentially ofutilizing any of the methodology disclosed herein. In another aspect,the disclosure provides for methods of producing anethol, (E)-anethol,or any one of compounds 3a-3l as set forth in Table 1 comprising,consisting of, or consisting essentially of utilizing the methods setforth in, for example, Scheme A, or any of the methods disclosed herein.The disclosure additionally provides for compositions comprising,consisting of, and consisting essentially of any of the disclosedcompounds, for example, anethol, (E)-anethol, or any one of compounds3a-3l as set forth in Table 1 as produced by the disclosed methods.

EXAMPLES Example 1

In this example, (E)-Anethol is prepared by the following procedure:Potassium allyltrifluoroborate (148.0 mg, 1.0 mmol), 4-bromoianisole (32L, 0.25 mmol), (a 4:1 ratio of potassium allyltrifluoroborate and4-bromoanisole respectively), K₂CO₃ (104.0 mg, 0.75 mmol) andPdCl₂(d^(t)bpf) (5.0 mg, 0.0075 mmol, 3 mol %) were placed in an argonflushed pyrex tube. The pyrex tube was capped with a rubber septum,flushed with argon and 2.5 mL of isopropanol/water (2:1) was added. Theresulting mixture in the pyrex tube was placed in a CEM microwave unitand allowed to irradiate at 120° C. for 30 minutes. As an example,preparation of (E)-Anethol by this method is set forth in FIG. 1.

After standard work-up by adding ammonium chloride and ethyl ether, theether layer was separated. The reaction mixture was adsorbed in a silicagel plate for preparative TLC with hexane as the eluent and thedeveloped TLC plate was exposed to a UV lamp and the intense spot forthe product was marked. The collected compound adsorbed in the silicagel was washed with ethyl ether, filtered, dried the filtrate to get thedesired product. The pure product (E)-Anethol was isolated in 97% yield.In another aspect, the preparative TLC the product can also be purifiedby subjected to silica gel chromatography using hexane as an eluent.

Example 2

In this example, Potassium allyltrifluoroborate 1 (93.0 mg, 0.625 mmol),4-bromoiodobenzene 2d (71.0 mg, 0.25 mmol), K2CO3 (104.0 mg, 0.75 mmol),and PdCl2(dtbpf) (0.0075 mmol, 3 mol %) were placed in an argon-flushedpyrex tube. The pyrex tube was capped with a rubber septum, flushed withargon, and 2.5 mL of isopropanol/water (2:1) was added.

The resulting mixture present in the pyrex tube was placed in a CEMmicrowave unit and allowed to irradiate at 120 C for 30 min. Afteradding ammonium chloride and ethyl ether, the ether layer was separated.The reaction mixture was adsorbed in silica gel and transferred into thecolumn and was subjected to silica gel chromatography using hexane as aneluent. The pure product 4-bromo-trans-b-methylstyrene, compound 3d(from Table 1) was isolated in a 95% yield (FIG. 4, Table 1, Entry 4) 1HNMR (CDCl₃, 300 MHz): d 7.22 (m, 4H, -4-Br—C6H4), 6.26 (d, J=16.8 Hz,1H), 6.24 (dq, J=15.8 Hz, 6.3 Hz, 1H) 1.80 (d, J=5.7 Hz, 3H). LRMSCalculated for C9H9Br M+197. Found: 197.

Example 3

In this example, in method A (see FIG. 3), a 1 to 2 ratio of potassiumallyltrifluoroborate 1 and 4-bromoiodobenzene (compound 2d from Table 1)along with 5 mol % of PdCl2(dppf)CH₂Cl₂ and 4 equiv of K2CO3 were addedin 1 M solution of isopropanol-water and refluxed for overnight. Thereaction progress was monitored by GC-MS. No allylation was observed butthe homo-coupling product 4,40-dibromo biphenyl, along with startingdihalo compounds, was observed.

Example 4

In this example, in method B, (see FIG. 3) changing the proportion ofpotassium allyltrifluoroborate 1 and 4-bromoiodobenzene (compound 2dfrom Table 1) to 1:1 along with the same loading of catalyst and base asset forth in Example 3 in isopropanol-water and the reaction mixtureirradiated under microwave heating system generated the allylatedproduct along with the double addition product shown previously inScheme 1. The reproducibility of this reaction was not reliable.

Example 5

In this example, switching to a new palladium salt PdCl2(dtbpf) inmethod C (see FIG. 3) led to a new catalyst system that performed in aselective monoallylation fashion. The combination of a PdCl2(dtbpf)catalyst, 4-bromoiodobenzene, K2CO3, and water-isopropanol undermicrowave irradiation for 30 min produced allyl coupling products withremarkable regioselectivity (FIG. 3, Scheme 2). The potassiumallyltrifluoroborate was prepared using the known method (See, forexample, Vedejs, et al. J. Org. Chem.1995, 60, 3024 and Batey et al.Tetrahedron Lett. 1999, 40, 4289, the contents of which are herebyincorporated by reference in their entirety) and was then treated withvarious dihalides such as 1,4-diiodobenzene (compound 2b from Table 1),4-chloroiodobenzene (compound 2c from Table 1), 4-bromoiodobenzene(compound 2d from Table 1), and 4-fluoroiodobenzene (compound 2e fromTable 1) applying method C. In each of the above cases, allylationreactions took place at the central carbon, b-carbon selectivity. Wheniodobenzene (compound 2a from Table 1) was employed the same selectivitywas observed. When the catalyst was used in excess the starting materialdisappeared rapidly but the homocoupled product predominated.

Example 6

In this example, the influence of substituents on aromatic rings,functional groups attached to the aryl rings, such as CF3, CN, and CH3,were introduced by following the reaction conditions described in methodC of Scheme 2. Reactions furnished successful cross-coupling allylationcompounds, 3f, 3g, and 3j with beta-carbon selectivity (FIG. 4, Table 1,Entries 6, 7, and 10). 3-Chloroiodobenzene (compound 2h from Table 1)and 3-bromoiodobenzene (compound 2i from Table 1), also gave thecorresponding trans-b-methylstyrenes (compounds 3h and 3i, respectively,from Table 1) (FIG. 4, Table 1, Entries 8 and 9).

The ratio of the central carbon selectivity with endo-productsArCH@CHCH3 (compounds 3a-3j from Table 1), and exo-products ArC(CH3)@CH24a-4j was 5:1. In case of 4-methyliodobenzene, (compound 2j from Table1), the ratio was 3:2 (FIG. 4, Table 1, Entry 10). The endo- andexo-products were unable to be separated by chromatography. Forsimplification, exo-products were not shown.

Example 7

In this example, 4-chlrobromobenzene, (compound 2k from Table 1) and3-chlorobromobenzene (compound 21 from Table 1), also underwent thecoupling reaction but selectivity was poor. C— or terminal carbonaddition products predominated along with b- or central carbon additionproducts (FIG. 4, Table 1, Entries 11 and 12). The ratio was c:b (3:2).It was noted that GC-MS analysis showed complete conversion to theproduct but when the reaction mixture was subjected to silica gelchromatography, some of the products were lost. Product volatility couldbe the cause of the loss. The highlighted part of this newtransformation is regioselectivity. The generally accepted mechanism forthis type of reaction involves nucleophilic attack on a cationicp-allylpalladium complex at the terminal or c-carbon, in some cases atthe a-carbon. Louis Hegedus's pioneering report on the carbanionattacking the central carbon of the p-allyl complex greatly supports thepresent observation. A reasonable mechanism for cyclopropanationinvolves direct nucleophilic attack on the central carbon of the p-allylsystem to form palladacyclobutane, followed by reductive elimination toproduce the cyclopropane which presumably isomerizes totrans-b-methylstyrene (FIG. 5, Scheme 3). Interestingly, when samereaction condition (method C) was applied to potassiumcrotyltrifluoroborates and aryl halides, coupling products witha-selectivity were predominated along with trace amount of c-adduct(FIG. 6, Scheme 4). Analytical data for beta-methylstyrenes of Table 1is set forth in FIG. 7.

1. A method of synthetically producing styrene by a reaction comprisingreacting a potassium trifluoroborate with an aryl halide compound ofFormula (I)

wherein X is selected from the group consisting of I, Br, OTf, ONf, ODs,and OAc; and Z is selected from the group consisting of F, Cl, Br, I,CN, —SO₃H, —CO₂H, —CHO, —NO₂, CF₃, CCl₃, and an alkyl group; and whereinsaid reaction is catalyzed by a palladium salt.
 2. The method of claim1, wherein said palladium salt is selected from the group consisting ofPd(OAc)₂, PdCl₂(dppf)CH₂Cl₂, PdCl₂ (d^(t)bpf), Pd₂(dba)CHCl₃ PdCl₂(dphos)₂, Pd(dba)₂, PdCl₂ (dtbpf), and Pd(Ph₃)₂.
 3. The method of claim1, wherein said potassium trifluoroborate is potassiumallyltrifluoroborate.
 4. The method of claim 1, wherein said styrene isa beta-methyl styrene.
 5. The method of claim 1, wherein said reactionfurther comprises heating said potassium trifluoroborate and said arylhalide from about 100° C.-150° C. for about 10 to about 60 minutes. 6.The method of claim 1, wherein said reaction produces a yield of styrenefrom about 80%-99%.
 7. The method of claim 1, wherein said potassiumtrifluoroborate and said aryl halide are in a ratio of about 4:1 toabout 1:1.
 8. A method of synthetically producing (E)-Anethol comprisingreacting a potassium allyltrifluoroborate with 4-bromoanisole.
 9. Themethod of claim 8, wherein the reaction is catalyzed by a palladiumsalt.
 10. The method of claim 9, wherein said palladium salt is selectedfrom the group consisting of Pd(OAc)₂, PdCl₂(dppf)CH₂Cl₂, PdCl₂(d^(t)bpf), Pd₂(dba)CHCl₃ PdCl₂ (dphos)₂, Pd(dba)₂, PdCl₂ (dtbpf), andPd(Ph₃)₂.
 11. The method of claim 9, wherein said palladium salt isPdCl₂(d^(t)bpf).
 12. The method of claim 8, wherein the reaction furthercomprises heating said potassium allyltrifluoroborate and said4-bromoanisole from about 100° C.-150° C. for about 10 to about 60minutes.
 13. The method of claim 8, wherein the reaction produces ayield of (E)-Anethol from about 80%-99%.
 14. The method of claim 8,wherein the reaction produces a yield of (E)-Anethol from about 90%-99%.15. The method of claim 8, wherein said potassium allyltrifluoroborateand said 4-bromoanisole are present in a ratio of about 5:1 to about1:5.
 16. The method of claim 8, wherein said potassiumallyltrifluoroborate and said 4-bromoanisole are present in a ratio ofabout 4:1 to about 1:2.
 17. The method of claim 8, wherein saidpotassium allyltrifluoroborate and said 4-bromoanisole are present in aratio of about 4:1 to about 1:1.
 18. The method of claim 8, wherein saidpotassium allyltrifluoroborate and said 4-bromoanisole are present in aratio of about 4:1.
 19. The method of claim 8, wherein said potassiumallyltrifluoroborate and said 4-bromoanisole are present in a ratio ofabout 4:1, the reaction is catalyzed by a palladium salt; and thereaction comprises heating said potassium allyltrifluoroborate and said4-bromoanisole from about 100° C.-150° C. for about 10 to about 60minutes.
 20. A method of administering (E)-Anethol to a patient in needthereof to treat a disorder selected from the group consisting of aviral infection, HIV, Hepatitis C, herpes simplex virus-1, herpessimplex virus-2, vesicular stomatitis virus, parainfluenza-3 coxsackieB3, and sindbid virus.